It has been estimated that 80-90% of all human cancers are caused by chemical carcinogens, many of which are present in the environment. Decisions regarding allowable levels of these environmental carcinogens are currently questionable because of uncertainty as to how these agents interact. It is the purpose of this proposal to examine the additive and synergistic effects of pairs of carcinogens and to attempt to establish criteria for understanding their combined effect. There is increasing evidence that carcinogenesis is initiated by base damage to DNA causing mutation. We shall therefore study the activity of carcinogens as mutagens using: 1) Two bacterial mutation assays a) a forward mutation assay measuring induction to 8-azaguanine resistance, b) a reversion assay using the Ames tester strains and 2) a mammalian cell (CHO) assay measuring forward mutation to thioguanine-resistance and ouabain-resistance. Dose-response curves of pairs of compounds with the concentration of one of them fixed will be compared with those of the individual substances. Pairs will be chosen according to the kind of DNA damage they cause (missense or frameshift mutations, monoadduct or diadduct damage) and in mammalian cells, according to the repair process they induce (short and long patch repair). Homologous and heterologous pairs chosen according to the first two criteria will be tested for reversion on strains containing either frameshift or missense mutations. Those combinations which show striking synergism in the bacterial assays will be further tested in mammalian cells to determine whether the same synergisms occur in mammalian cells and to what extent the results of bacterial tests can be extended to mammalian systems. This information should provide guidelines to assess whether exposure to multiple agents in the environment is likely to present unanticipated hazards to humans.